The present invention relates, in general, to atmospheric pressure ionization techniques, and more particularly to an interface structure which utilizes atmospheric pressure ionization techniques such as electrospray, ion spray, and corona discharge ionization in combination with a mass analyzer.
The development of various spray techniques for forming ions from analytes was a significant advance in the field of mass spectrometry, for these techniques, and particularly those that employ electric fields to impart charges to droplets in the spray, permit the formation of highly charged ions (particles) from high molecular weight species. These highly charged ions are characterized by mass/charge ratios that are well within the range of values accessible to most modern mass analyzers.
In addition, the combination of mass analyzers with on-line separation methods, such as liquid chromatography, for mixtures in solution is becoming increasingly important. Mass spectrometry has long been recognized for its high sensitivity, but its use as a detector in combination with on-line separators of condensed-phase analytes has been limited at least in part because of the incompatibility of mass spectrometry to commonly used reversed-phase high-performance liquid chromatography (HPLC). The incompatibility arises, in part, from the use of a wide variety of buffer additives in the conventional HPLC eluent, high percentages of water in the eluent, and flow rates that are typically maintained at 1 mL/min., with standard 4.6 mm inner diameter HPLC columns. The HPLC eluent composition and its flow rate into the mass spectrometer have challenged the development of a routine and analytically rugged interface between the HPLC column and the mass spectrometer (LC/MS interface).
Historically, electron ionization (EI) mass spectra were produced from solutions introduced into a mass spectrometer at less than one microliter (.mu.L) per minute. Later, chemical ionization (CI) mass spectra were generated by the introduction of aqueous solutions at 1-5 .mu.L/min. into a CI mass spectrometer ion source. For this early work, the direct liquid introduction LC/MS interface was developed and commercially marketed through the early 1980's. This approach produced a modest beginning for LC/MS problem solving in several areas, but its limitation was the need for a 100-1 post column split, as described by J. D. Henion, "Drug Analysis by Continuously Monitored Liquid Chromatography/Mass Spectrometry with a Quadrupole Mass Spectrometer", Analytical Chemistry, 1978, No. 50, pp. 1687-1693, or the use of micro HPLC techniques, as described by Lee et al, Journal of Chromatography Science, 1986, No. 23, pp. 253-264. These were due to the vacuum pumping limitations imposed by conventional mass spectrometers. Thus, the liquid flow introduced into the CI ion source of these systems was limited to about 5 .mu.L/min., and this limitation and the experimental difficulties associated with it discouraged many potentially interested researchers in the early days of LC/MS.
The introduction of thermospray LC/MS in the mid 1980's offered a significant breakthrough to the previous flow limitations discussed above. Thermospray LC/MS offered the realistic possibility of using conventional HPLC flows of 1.0-1.5 mL/min. with high aqueous eluent composition and volatile buffer additives such as ammonium acetate. The total HPLC effluent could be introduced into the mass spectrometer without the need for a post-column split or the use of micro HPLC techniques. Although the thermospray LC/MS approach offered an apparent simplification of the process in addition to providing three different modes of ionization, it was later learned that there could be a number of problems with the technique. These included widely varying response to different analytes, the need for different temperature settings for varying experimental conditions, thermal breakdown of some labile compounds, and the lack of structurally informative mass spectral information. Some of these needs were addressed with the introduction of particle beam LC/MS techniques which provided EI and CI mass spectra using HPLC flows in the neighborhood of 0.5 mL/min. However, this approach to LC/MS suffers from some limitations with regard to trace analyses and extends to involatile compounds of only slightly higher molecular weight, than can be handled by capillary gas chromatography/mass spectrometry (GC/MS).
Recently, considerable interest has developed in electrospray ionization as a new means of handling intractable, higher molecular weight compounds. Following initial results that demonstrated very good sensitivity for polar and high molecular weight compounds, interest has developed in combining HPLC with electrospray mass spectrometry. Unfortunately, however, electrospray returned the art to the very slow HPLC flow rates originally produced by the direct liquid introduction LC/MS interface described above. In particular, pure electrospray currently is limited to effluent flows of 1-5 .mu.L/min. More recently with implementation pneumatically assisted electrospray [A. P. Bruins et al, Anal. Chem., v.59, p.2642(1987)] higher flow (up to 50 .mu.L rates) became routine in practice of HPLC- mass spectrometry. However, at higher flow rate significant chemical noise causes problems: more solvated ions entering the mass spectrometer thus resulting in more noisy mass spectra as well as micro droplets produced by the spray at higher flow rates tend to plug the ion sampling orifice and produce random "spikes" in the chromatographic profile. This behavior is not acceptable, and it is preferred to use conventional HPLC flows of 1-1.5 mL/min. without any additional experimental constraints, while still obtaining low nanogram or better detection limits.